Plasma Tranexamic Acid Concentrations Research Articles

Population pharmacokinetic modelling and simulation of tranexamic acid in adult trauma patients.

The aim of this study is to describe the disposition of tranexamic acid (TXA) in adult trauma patients and derive a dosing regimen that optimizes exposure based on a predefined exposure target. We performed a population pharmacokinetic (popPK) analysis of participants enrolled in the Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury (TAMPITI) trial (≥18 years with traumatic injury, given ≥1 blood product and/or requiring immediate transfer to the operating room) who were randomized to a single dose of either 2 or 4g of TXA ≤2h from time of injury. PopPK analysis was conducted using nonlinear mixed-effects modelling (NONMEM). Simulations were then performed using the final model to generate estimated plasma TXA concentrations in 1000 simulated participants. Dosing schemes were evaluated to determine maintenance of TXA plasma concentrations >10mg/L for ≥8h after administration of the initial dose. TXA PK was best described by a two-compartment model with proportional residual error and allometric scaling on all parameters. Platelet count, skeletal muscle oxygen saturation measured by near-infrared spectroscopy and interleukin-8 concentration were significant covariates on TXA clearance. Based on simulations, a 2g IV bolus dose, repeated 3h later, best achieved the target exposure. According to simulations from a popPK model of TXA, a 2g IV bolus with a repeated dose 3h later would be most likely to maintain concentrations >10mg/L for 8h in >95% of adult trauma patients and should be considered for patients with ongoing haemorrhage.

Ruggedized Self-Propelling Hemostatic Gauze Delivers Low Dose of Thrombin and Systemic Tranexamic Acid and Achieves High Survival in Swine With Junctional Hemorrhage.

Hemorrhage is responsible for 91% of preventable prehospital deaths in combat. Bleeding from anatomic junctions such as the groin, neck, and axillae make up 19% of these deaths, and reports estimate that effective control of junctional hemorrhage could have prevented 5% of fatalities in Afghanistan. Hemostatic dressings are effective but are time-consuming to apply and are limited when proper packing and manual pressure are not feasible, such as during care under fire. CounterFlow-Gauze is a hemostatic dressing that is effective without compression and delivers thrombin and tranexamic acid into wounds. Here, an advanced prototype of CounterFlow-Gauze, containing a range of low thrombin doses, was tested in a lethal swine model of junctional hemorrhage. Outcomes were compared with those of Combat Gauze, the current dressing recommended by Tactical Combat Casualty Care. CounterFlow-Gauze containing thrombin doses of 0, 20, 200, and 500 IU was prepared. Swine received femoral arteriotomies, and CounterFlow-Gauze was packed into wounds without additional manual compression. In a separate study using a similar model of junctional hemorrhage without additional compression, CounterFlow-Gauze containing 500 IU thrombin was tested and compared with Combat Gauze. In both studies, the primary outcomes were survival to 3 h and volume of blood loss. CounterFlow-Gauze with 200 and 500 IU had the highest 3-h survival, achieving 70 and 75% survival, respectively. CounterFlow-Gauze resulted in mean peak plasma tranexamic acid concentrations of 9.6 ± 1.0 µg/mL (mean ± SEM) within 3 h. In a separate study with smaller injury, CounterFlow-Gauze with 500 IU achieved 100% survival to 3 h compared with 92% in Combat Gauze animals. An advanced preclinical prototype of CounterFlow-Gauze formulated with a minimized thrombin dose is highly effective at managing junctional hemorrhage without compression. These results demonstrate that CounterFlow-Gauze could be developed into a feasible alternative to Combat Gauze for hemorrhage control on the battlefield.

Tranexamic Acid Administered During Cesarean Delivery in High-risk Patients: Maternal Pharmacokinetics, Pharmacodynamics, and Coagulation Status

(Am J Obstet Gynecol. 2022;S0002-9378(22)00441-0) Tranexamic acid (TXA) is often used to prevent or reduce postpartum hemorrhage (PPH), reducing the risk of maternal mortality and decreasing the blood transfusion rate. TXA is widely used in clinical practice, but dosing and covariates that affect the effectiveness of the drug have yet to be studied in the obstetric population. The purpose of this study was to evaluate the pharmacokinetics and pharmacodynamics of the current recommended 1 g intravenous dosage of TXA typically administered during cesarean delivery, and in conjunction use rotational thromboelastometry to assess clot formation and fibrinolysis in patients with high risk of PPH. The primary aim was to evaluate the central tendency and variability of TXA plasma concentrations in high-risk patients after the standard dose up to 5 hours after delivery. Secondary aims were to estimate the correlation between TXA plasma concentrations and body mass index, assess coagulation measurements using rotational thromboelastometry, and other outcomes related to PPH, such as changes in hemoglobin and the requirement of blood transfusions.

Absence of Hyperactivation of Fibrinolysis Explains the Lack of Hemostatic Efficacy of Prophylactic Tranexamic Acid (TXA) in Hypoproliferative Thrombocytopenia

Background: We previously reported the results of the A-TREAT study (American Trial Using Tranexamic Acid in Thrombocytopenia: NCT02578901). This randomized double-blind placebo-controlled trial demonstrated that TXA administration is not superior to placebo in preventing WHO grade 2 or higher bleeding in severely thrombocytopenic patients requiring supportive platelet transfusion following myeloablative therapy for hematologic disorders (Gernsheimer T., ASH 2020 Plenary Session).Here, we present results of the A-TREAT ancillary study - Fibrinolysis Evaluation in A-TREAT (FEAT). Blood samples were collected from a subset (n=115) of A-TREAT participants just prior to initiation of study drug (when the platelet count was <30,000/µl) and at a later time point when TXA was at a steady state trough level (5 ±2 days following study drug initiation). Using global assays of fibrinolysis in plasma, our a priori hypotheses were that: 1] a baseline ‘hyperfibrinolytic’ profile would be associated with a higher proportion of grade 2+ bleeding; and 2] trough TXA levels would be associated with a ‘hypofibrinolytic’ profile and a lower proportion of grade 2+ bleeding.Methods: Fibrinolysis in platelet-free citrated plasma was assessed by 3 global assays: euglobulin clot lysis time (ECLT), plasmin generation (PG), and tPA resistance clot lysis time (tPA-CLT) using previously described methods (Ilich A. RPTH 2020, Miszta A. JTH 2021). Trough plasma TXA concentration was measured using a validated tandem mass spectrometry assay. Individual fibrinolytic analytes (PAI-1, tPA, plasminogen, alpha2-antiplasmin and plasmin-antiplasmin complexes) were quantified by ELISA.Results: Baseline samples did not demonstrate a hyperfibrinolytic profile by ECLT. To the contrary, ECLT values were significantly increased compared to healthy controls (figure 1). Furthermore, none of the measured fibrinolytic parameters (ECLT, tPA-CLT, total PAI-1, tPA, plasminogen, alpha2-antiplasmin or plasmin-antiplasmin complexes) at baseline were associated with a greater risk of grade 2+ bleeding during follow up, regardless of treatment arm. On the follow-up samples, neither pharmacokinetic (trough TXA concentration) nor pharmacodynamic parameters (PG or tPA-CLT) were associated with bleeding severity. A high inter-patient variability of TXA trough concentrations was noted in the treatment arm (min-max: 0.7-10 ug/ml), and drug levels correlated strongly with global fibrinolysis assessment by PG (Spearman r, -0.78, 95% CI -0.88 - -0.62) and tPA-CLT (r, 0.74, 0.56 - 0.85) (figure 2).Conclusions:1] No evidence of fibrinolytic hyperactivation was observed in these thrombocytopenic patients;2] trough TXA concentrations varied significantly between patients receiving the same dosing schedule; and3] tPA-CLT and PG parameters correlated well with TXA plasma concentrations and thus may be used to estimate the extent of fibrinolytic inhibition in patients treated with TXA.Discussion: The absence of hyperactivation of endogenous fibrinolysis in this study is in contrast to our recent findings in trauma. Specifically, we reported that almost half of trauma patients demonstrated evidence of fibrinolytic hyperactivation (by ECLT) on admission (Ilich A. Thromb Res, 2021). Since TXA has been shown to reduce mortality due to bleeding in trauma (CRASH II, Lancet, 2010) and given that baseline hyperfibrinolysis is common in trauma, we hypothesize that the absence of fibrinolytic hyperactivation observed in the A-TREAT study patients likely explains the clinical lack of efficacy of TXA. [Display omitted] DisclosuresGernsheimer: Amgen: Honoraria; Novartis: Honoraria; Principia: Research Funding; Rigel: Research Funding; Cellphire: Consultancy; Dova: Consultancy; Sanofi: Consultancy. Triulzi: Fresenius Kabi: Membership on an entity's Board of Directors or advisory committees; Realta: Membership on an entity's Board of Directors or advisory committees. Wolberg: CSL Behring: Consultancy; Bristol Myers Squibb: Research Funding; Takeda: Research Funding. Key: Takeda: Research Funding; BioMarin: Honoraria, Other: Participation as a clinical trial investigator; Sanofi: Consultancy; Grifols: Research Funding; Uniqure: Consultancy, Other: Participation as a clinical trial investigator.

Physiologically based modelling of tranexamic acid pharmacokinetics following intravenous, intramuscular, sub-cutaneous and oral administration in healthy volunteers

Background: Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post-partum haemorrhage. Treatment success is dependant on early intervention and rapid systemic exposure to TXA. The requirement for intravenous (IV) administration can in some situations limit accessibility to TXA therapy. Here we employ physiologically based pharmacokinetic modelling (PBPK) to evaluate if adequate TXA exposure maybe achieved when given via different routes of administration. Methods: A commercially available PBPK software (GastroPlus®) was used to model published TXA pharmacokinetics. IV, oral and intramuscular (IM) models were developed using healthy volunteer PK data from twelve different single dose regimens (n = 48 participants). The model was verified using separate IV and oral validation datasets (n = 26 participants). Oral, IM and sub-cutaneous (SQ) dose finding simulations were performed. Results: Across the different TXA regimens evaluated TXA plasma concentrations varied from 0.1 to 94.0 µg/mL. Estimates of the total plasma clearance of TXA ranged from 0.091 to 0.104 L/h/kg, oral bioavailability from 36 to 67% and Tmax from 2.6 to 3.2 and 0.4 to 1.0 h following oral and intramuscular administration respectively. Variability in the observed TXA PK could be captured through predictable demographic effects on clearance, combined with intestinal permeability and stomach transit time following oral administration and muscle blood flow and muscle/plasma partition coefficients following intra-muscular dosing. Conclusions: This study indicates that intramuscular administration is the non-intravenous route of administration with the most potential for achieving targeted TXA exposures. Plasma levels following an IM dose of 1000 mg TXA are predicted to exceed 15 mg/mL in < 15 min and be maintained above this level for approximately 3 h, achieving systemic exposure (AUC0–6) of 99 to 105 µg*hr/mL after a single dose. Well-designed clinical trials to verify these predictions and confirm the utility of intramuscular TXA are recommended.

Optimal Tranexamic Acid Dosing Regimen in Cardiac Surgery: What Are the Missing Pieces?

Optimal Tranexamic Acid Dosing Regimen in Cardiac Surgery: What Are the Missing Pieces?

Optimal use of intravenous tranexamic acid for hemorrhage prevention in pregnant women

Every 2 minutes, there is a pregnancy-related death worldwide, with one-third caused by severe postpartum hemorrhage. Although international trials demonstrated the efficacy of 1000 mg tranexamic acid in treating postpartum hemorrhage, to the best of our knowledge, there are no dose-finding studies of tranexamic acid on pregnant women for postpartum hemorrhage prevention. This study aimed to determine the optimal tranexamic acid dose needed to prevent postpartum hemorrhage. We enrolled 30 pregnant women undergoing scheduled cesarean delivery in an open-label, dose ranging study. Subjects were divided into 3 cohorts receiving 5, 10, or 15 mg/kg (maximum, 1000 mg) of intravenous tranexamic acid at umbilical cord clamping. The inclusion criteria were ≥34 week's gestation and normal renal function. The primary endpoints were pharmacokinetic and pharmacodynamic profiles. Tranexamic acid plasma concentration of >10 μg/mL and maximum lysis of <17% were defined as therapeutic targets independent to the current study. Rotational thromboelastometry of tissue plasminogen activator-spiked samples was used to evaluate pharmacodynamic profiles at time points up to 24 hours after tranexamic acid administration. Safety was assessed by plasma thrombin generation, D-dimer, and tranexamic acid concentrations in breast milk. There were no serious adverse events including venous thromboembolism. Plasma concentrations of tranexamic acid increased in a dose-proportional manner. The lowest dose cohort received an average of 448±87 mg tranexamic acid. Plasma tranexamic acid exceeded 10 μg/mL and maximum lysis was <17% at >1 hour after administration for all tranexamic acid doses tested. Median estimated blood loss for cohorts receiving 5, 10, or 15 mg/kg tranexamic acid was 750, 750, and 700 mL, respectively. Plasma thrombin generation did not increase with higher tranexamic acid concentrations. D-dimer changes from baseline were not different among the cohorts. Breast milk tranexamic acid concentrations were 1% or less than maternal plasma concentrations. Although large randomized trials are necessary to support the clinical efficacy of tranexamic acid for prophylaxis, we propose an optimal dose of 600 mg in future tranexamic acid efficacy studies to prevent postpartum hemorrhage.

Functional Testing for Tranexamic Acid Duration of Action Using Modified Viscoelastometry

Introduction: Tranexamic acid (TXA) is the standard medication to prevent or treat hyperfibrinolysis. However, prolonged inhibition of lysis (so-called “fibrinolytic shutdown”) correlates with increased mortality. A new viscoelastometric test enables bedside quantification of the antifibrinolytic activity of TXA using tissue plasminogen activator (TPA). Materials and Methods: Twenty-five cardiac surgery patients were included in this prospective observational study. In vivo, the viscoelastometric TPA test was used to determine lysis time (LT) and maximum lysis (ML) over 96 h after TXA bolus. Additionally, plasma concentrations of TXA and plasminogen activator inhibitor 1 (PAI-1) were measured. Moreover, dose effect curves from the blood of healthy volunteers were performed in vitro. Data are presented as median (25–75th percentile). Results: In vivo TXA plasma concentration correlated with LT (r = 0.55; p < 0.0001) and ML (r = 0.62; p < 0.0001) at all time points. Lysis was inhibited up to 96 h (LT_TPA-test: baseline: 398 s [229–421 s] vs. at 96 h: 886 s [626–2,175 s]; p = 0.0013). After 24 h, some patients (n = 8) had normalized lysis, but others (n = 17) had strong lysis inhibition (ML <30%; p < 0.001). The high- and low-lysis groups differed regarding kidney function (cystatin C: 1.64 [1.42–2.02] vs. 1.28 [1.01–1.52] mg/L; p = 0.002) in a post hoc analysis. Of note, TXA plasma concentration after 24 h was significantly higher in patients with impaired renal function (9.70 [2.89–13.45] vs.1.41 [1.30–2.34] µg/mL; p < 0.0001). In vitro, TXA concentrations of 10 µg/mL effectively inhibited fibrinolysis in all blood samples. Conclusions: Determination of antifibrinolytic activity using the TPA test is feasible, and individual fibrinolytic capacity, e.g., in critically ill patients, can potentially be measured. This is of interest since TXA-induced lysis inhibition varies depending on kidney function.

Functional testing for tranexamic acid effect duration using modified viscoelastometry

Introduction Tranexamic acid (TXA) is considered gold standard for treatment and prophylaxis of hyperfibrinolysis in trauma patients and cardiac surgery [1,2]. However, prolonged inhibition of lysis (so-called “fibrinolytic shutdown”) correlates with increased mortality in critical ill patients [3]. Additionally, there is still an ongoing discussion about minimal plasma concentrations, effect duration and dose reduction in renal dysfunction [4]. A new viscoelastometric test enables bedside quantification of the antifibrinolytic activity of TXA using tissue plasminogen activator (TPA) and could therefore be useful in dosage and administration of TXA. Methods 25 cardiac surgery patients were included in this prospective observational trial. In-vivo, viscoelastometric TPA-test was used to determine Lysis Time (LT) and Maximum Lysis (ML) over 96h after TXA bolus. Additionally, TXA plasma concentration and plasminogen-activator-inhibitor-1 (PAI-1) were measured. Moreover, dose-effect-curves from blood of healthy volunteers were performed in-vitro. Data presented as median with 25-75th percentiles. Results In-vivo at all timepoints TXA plasma concentration correlated with LT (r=0.55; p Discussion Determination of antifibrinolytic activity using TPA-test is feasible. This is of interest since TXA-induced lysis inhibition varies depending on kidney function. In future, the individual fibrinolytic capacity, e.g. in critically ill patients, can be measured and TXA dosage can be adapted. Our in vitro results supports recent recommendations that TXA plasma concentrations of 10-15µg/ml are sufficient to inhibit fibrinolysis.

Functional testing of tranexamic acid effects in patients undergoing elective orthopaedic surgery.

Tranexamic acid (TXA) can reduce blood loss and transfusion rates in orthopaedic surgery. In this regard, a new viscoelastometric test (TPA-test, ClotPro), enables the monitoring of TXA effects. This prospective observational study evaluated and correlated TXA plasma concentrations (cTXA) following intravenous and oral administration in patients undergoing elective orthopaedic surgery with lysis variables of TPA-test. Blood samples of 42 patients were evaluated before TXA application and 2, 6, 12, 24 and 48h afterwards. TPA-test was used to determine lysis time (LT) as well as maximum lysis (ML) and cTXA was measured using Ultra-High-Performance-Liquid-Chromatography/Mass-Spectrometry. Data are presented as median (min-max). LTTPA-test and MLTPA-test correlated with cTXA (r = 0.9456/r = 0.5362; p < 0.0001). 2h after intravenous TXA administration all samples showed complete lysis inhibition (LTTPA-test prolongation: T1: 217s (161-529) vs. T2: 4500s (4500-4500);p < 0.0001), whereas after oral application high intraindividual variability was observed as some samples showed only moderate changes in LTTPA-test (T1: 236s (180-360) vs. T2: 4500s (460-4500); p < 0.0001). Nevertheless, statistically LTTPA-test did not differ between groups. MLTPA-test differed 2h after application (i.v.: 9.0% (5-14) vs. oral: 31% (8-97); p = 0.0081). In 17/21 samples after oral and 0/21 samples after intravenous administration cTXA was < 10µgml-1 2h after application. TPA-test correlated with cTXA. MLTPA-test differed between intravenous and oral application 2h after application. Most patients with oral application had TXA plasma concentration < 10µgml-1. The duration of action did not differ between intravenous and oral application. Additional studies evaluating clinical outcomes and side-effects based on individualized TXA prophylaxis/therapy are required.

S4A-02 SESSION 4A: GENERALITIES IN CRANIOSYNOSTOSIS – PART I EFFICACY OF TWO TRANEXAMIC ACID DOSAGE REGIMES FOR CRANIOSYNOSTOSIS SURGERY; A RANDOMIZED CONTROLLED EQUIVALENCY TRIAL.

Introduction: Tranexamic acid (TXA) in a dose of 50 mg/kg loading dose followed by 5 mg/kg/h maintenance infusion has been shown to significantly reduce blood loss and blood transfusion in pediatric open craniosynostosis surgery compared with placebo. TXA plasma concentrations with this dosing regimen were shown to exceed the accepted therapeutic level by over 10 fold. From pharmacokinetic modeling, we predicted that reducing the loading dose to 10 mg/kg is adequate to maintain plasma concentrations above the presumed accepted therapeutic level of 20 mcg/mL. This may be safer in terms of side effect profile. The hypothesis of this study is to validate our TXA pharmacokinetic model and determine if the lower dosage scheme is as effective as the higher dosage scheme in decreasing blood loss and transfusion requirements in pediatric craniosynostosis surgery. Methods: With IRB (P00008434) and Ethic (2013-001056-35) approval, patients were consented and enrolled in a two-center, prospective, double-blind equivalence randomized controlled trial to compare high TXA dose (50mg/kg/15min and 5mg/kg/h) vs a lower TXA dose (10 mg/kg/15min and 5 mg/kg/h) regime. Standardized anesthetic, fluid, blood and blood product management protocols were followed. TXA analysis was performed by the Boston Children’s Hospital Pharmacokinetic Laboratory using liquid chromatography with mass spectrometry detection (LC/MS). An a priori non-inferiority margin of -20 mL/kg and -10 mL/kg was set in the analysis of blood loss and transfusion respectively. The two participating hospitals were: Boston Children’s Hospital, Boston USA, and Istituto Gaslini, Genoa, Italy. ClinicalTrials.gov identifier: NCT02188576. Results: Sixty-eight children, 3 months to 2 years scheduled for open craniosynostosis surgery were included. Demographics were comparable between groups. There was no significant difference in blood loss (39.4 vs 40.3 mL/kg) or blood transfusion (PRBC 23.3 vs 29.9 mL/kg) between the high and lower dose groups respectively. TXA plasma levels at steady state averaged 50 mcg/mL in the high dose vs 25 mcg/mL the lower dose group; both above the presumed therapeutic threshold. Blood loss and blood transfusion were also less than our previous study by two-fold. No adverse events such as seizures or thromboembolic events were observed in either group. Conclusion: A tranexamic acid dose regimen of 10 mg/kg loading dose and 5 mg/kg/h maintenance dose is as effective (non-inferior) as a higher dose regime of 50 mg/kg loading dose and 5 mg/kg/h maintenance infusion rate in reducing blood loss and transfusion requirements in pediatric craniosynostosis reconstruction surgery.

Tranexamic Acid Dosing for Cardiac Surgical Patients With Chronic Renal Dysfunction: A New Dosing Regimen.

Tranexamic acid (TXA) is a common antifibrinolytic agent used to minimize bleeding in cardiac surgery. Up to 50% cardiac surgical patients have chronic renal dysfunction (CRD). Optimal dosing of TXA in CRD remains poorly investigated. This is important as TXA is renally eliminated with accumulation in CRD. High TXA doses are associated with postoperative seizures. This study measures plasma TXA concentrations in CRD cardiac surgical patients for pharmacokinetic modeling and dose adjustment recommendations. This prospective cohort study enrolled 48 patients with stages 1-5 CRD, classified by Kidney Disease Outcome Quality Initiative. Patients were separated into 2 treatment groups. A "low-risk" group underwent simple aortocoronary bypass or single-valve repair/replacement and received a 50 mg/kg TXA bolus. A "high-risk" group underwent redo, aortic, multiple valve or combination surgery and received the Blood Conservation Using Anti-fibrinolytics Trial dosing regimen (loading dose 30 mg/kg, infusion 16 mg/kg/h with 2 mg/kg in pump prime). Primary outcome identified changes in TXA clearance and distribution volume, which provided the rationale for dose adjustment. Descriptive clinical outcomes assessed postoperative seizures, blood loss, ischemic-thrombotic complications, in-hospital mortality, and length of hospital stay. TXA concentrations were elevated and sustained above the therapeutic threshold for approximately 12 hours in high-risk stages 3-5 groups, in accordance to CRD severity. Using a pharmacokinetic model, we propose a simple new TXA dosing regimen that optimizes maximal antifibrinolysis and avoids excessive drug dosing.

No intravenous access, no problem: Intraosseous administration of tranexamic acid is as effective as intravenous in a porcine hemorrhage model.

The acute coagulopathy of trauma is often accompanied by hyperfibrinolysis. Tranexamic acid (TXA) can reverse this phenomenon, and, when given early, decreases mortality from bleeding. Establishing intravenous (IV) access can be difficult in trauma and intraosseous (IO) access is often preferred for drug administration. Currently, there are no data on the efficacy of IO administered TXA. Our objectives were to compare serum concentrations of TXA when given IV and IO and to compare the efficacy of IO administered TXA to IV at reversing hyperfibrinolysis. Using a porcine hemorrhage and ischemia-reperfusion model, 18 swine underwent hemorrhagic shock followed by a tissue plasminogen activator infusion to induce hyperfibrinolysis. Animals then received an IV or tibial IO infusion of TXA over 10 minutes. Blood was then analyzed using rotational thromboelastometry to monitor reversal of hyperfibrinolysis. Serum was analyzed for drug concentrations. After hemorrhage and ischemia-reperfusion, there were no significant differences in mean arterial pressure (48 vs. 49.5), lactate (11.1 vs. 10.8), and pH (7.20 vs. 7.22) between groups. Intraosseous TXA corrected the lysis index at 30 minutes in EX-TEM and IN-TEM, like IV infusion. Peak serum levels of TXA after IV and IO administration show concentrations of 160.9 μg/mL and 132.57 μg/mL respectively (p = 0.053). Peak levels occurred at the completion of infusion. Drug levels were tracked for four hours. At the end of monitoring, plasma concentrations of TXA were equivalent. Intraosseous administration of TXA is as effective as IV in reversing hyperfibrinolysis in a porcine model of hemorrhagic shock. Intraosseous administration was associated with a similar peak levels, pharmacokinetics, and clearance. Intraosseous administration of TXA can be considered in hemorrhagic shock when IV access cannot be established.

Is tranexamic acid exposure related to blood loss in hip arthroplasty? A pharmacokinetic-pharmacodynamic study.

Tranexamic acid (TXA) is an antifibrinolytic agent, decreasing blood loss in hip arthroplasty. The present study investigated the relationship between TXA exposure markers, including the time above the in vitro threshold reported for inhibition of fibrinolysis (10mg l-1 ), and perioperative blood loss. Data were obtained from a prospective, double-blind, parallel-arm, randomized superiority study in hip arthroplasty. Patients received a preoperative intravenous bolus of TXA 1g followed by a continuous infusion of either TXA 1g or placebo over 8h. A population pharmacokinetic study was conducted to quantify TXA exposure. In total, 827 TXA plasma concentrations were measured in 166 patients. A two-compartment model fitted the data best, total body weight determining interpatient variability in the central volume of distribution. Creatinine clearance accounted for interpatient variability in clearance. At the end of surgery, all patients had TXA concentrations above the therapeutic target of 10mg l-1 . The model-estimated time during which the TXA concentration was above 10mg l-1 ranged from 3.3h to 16.3h. No relationship was found between blood loss and either the time during which the TXA concentration exceeded 10mg l-1 or the other exposure markers tested (maximum plasma concentration, area under the concentration-time curve). In hip arthroplasty, TXA plasma concentrations were maintained above 10mg l-1 during surgery and for a minimum of 3h with a preoperative TXA dose of 1g. Keeping TXA concentrations above this threshold up to 16h conferred no advantage with regard to blood loss.

Comparison of tranexamic acid plasma concentrations when administered via intraosseous and intravenous routes

IntroductionThere is a lack of information regarding intraosseous (IO) administration of tranexamic acid (TXA). Our hypothesis was that a single bolus IO injection of TXA will have a similar pharmacokinetic profile to TXA administered at the same dose IV. MethodsSixteen male Landrace cross swine (mean body weight 27.6±2.6kg) were divided into an IV group (n=8) and an IO group (n=8). Each animal received 30mg/kg TXA via an IV or IO catheter, respectively. Jugular blood samples were collected for pharmacokinetic analysis over a 3h period. The maximum TXA plasma concentration (Cmax) and corresponding time as well as distribution half-life, elimination half-life, area under the curve, plasma clearance and volume of distribution were calculated. One- and two-way analysis of variance for repeated measures (time, group) with Tukey's and Bonferonni post hoc tests were used to compare TXA plasma concentrations within and between groups, respectively. ResultsPlasma concentrations of TXA were significantly higher (p<0.0001) in the IV group during the TXA infusion. Cmax occurred at 4min after initiation of the bolus in the IV group (9.36±3.20ng/μl) and at 5min after initiation of the bolus in the IO group (4.46±0.49ng/μl). Plasma concentrations were very similar from the completion of injection onwards. There were no significant differences between the two administration routes for any other pharmacokinetic variables measured. ConclusionThe results of this study support pharmacokinetic bioequivalence of IO and IV administration of TXA.

Pharmacokinetics of Tranexamic Acid in Neonates, Infants, and Children Undergoing Cardiac Surgery With Cardiopulmonary Bypass

Background Tranexamic acid (TXA) is one of the most commonly used antifibrinolytic medications in children undergoing repair of congenital heart defects. However, a pharmacokinetics analysis of TXA has never been performed in neonates or young children undergoing complex cardiac surgeries using cardiopulmonary bypass, hypothermia, circulatory arrest, and ultrafiltration. A comprehensive pharmacokinetics study was performed in this patient population. Methods Fifty-five patients ranging from 2 days through 4 yr old were categorized into three groups: children less than 2 months old, infants 2 months to 1 yr old, and children greater than 1 yr old and weighing up to 20 kg. TXA was given as a bolus of 100 mg/kg followed by an infusion of 10 mg · kg · h throughout the surgery. A dose of 100 mg/kg was placed in the cardiopulmonary bypass prime. A total of 16 to 18 samples were obtained from all patients throughout surgery. Plasma TXA concentrations were measured by high-performance liquid chromatography and modeled under a nonlinear mixed-effects framework with a two-compartment structural model. Results Cardiopulmonary bypass had a statistically significant impact on all pharmacokinetic parameters. Age was a better covariate than body weight, affecting both the distribution and the elimination of TXA. However, weight performed well in some cases. Other covariates including body surface area, pump prime volume, ultrafiltrate volume, and body temperature did not improve the model. Conclusions This TXA pharmacokinetic analysis is reported for the first time in neonates and young children undergoing complex cardiac surgeries with cardiopulmonary bypass. Dosing recommendations are provided as guidance for maintaining desired target concentrations.

Pharmacokinetic modeling of tranexamic acid for patients undergoing cardiac surgery with normal renal function and model simulations for patients with renal impairment.

Tranexamic acid (TXA), an effective anti-fibrinolytic agent that is cleared by glomerular filtration, is used widely for cardiopulmonary bypass (CPB) surgery. However, an effective dosing regimen has not been fully developed in patients with renal impairment. The aims of this study were to characterize the inter-patient variability associated with pharmacokinetic parameters and to recommend a new dosing adjustment based on the BART dosing regimen for CPB patients with chronic renal dysfunction (CRD). Recently published data on CPB patients with normal renal function (n = 15) were re-examined with a two-compartment model using the ADAPT5 and NONMEMVII to identify covariates that explain inter-patient variability and to ascertain whether sampling strategies might affect parameter estimation. A series of simulations was performed to adjust the BART dosing regimen for CPB patients with renal impairment. Based on the two-compartmental model, the number of samples obtained after discontinuation of TXA infusion was found not to be critical in parameter estimation (p > 0.05). Both body weight and creatinine clearance were identified as significant covariates (p < 0.005). Simulations showed significantly higher than normal TXA concentrations in CRD patients who received the standard dosing regimen in the BART trial. Adjustment of the maintenance infusion rate based on the percent reduction in renal clearance resulted in predicted plasma TXA concentrations that were safe and therapeutic (~100 mg·L(-1) ). Our proposed dosing regimen, with consideration of renal function, is predicted to maintain effective target plasma concentrations below those associated with toxicity for patients with renal failure for CPB.

Pharmacokinetics of tranexamic acid in neonates, infants, and children undergoing cardiac surgery with cardiopulmonary bypass.

Tranexamic acid (TXA) is one of the most commonly used antifibrinolytic medications in children undergoing repair of congenital heart defects. However, a pharmacokinetics analysis of TXA has never been performed in neonates or young children undergoing complex cardiac surgeries using cardiopulmonary bypass, hypothermia, circulatory arrest, and ultrafiltration. A comprehensive pharmacokinetics study was performed in this patient population. Fifty-five patients ranging from 2 days through 4 yr old were categorized into three groups: children less than 2 months old, infants 2 months to 1 yr old, and children greater than 1 yr old and weighing up to 20 kg. TXA was given as a bolus of 100 mg/kg followed by an infusion of 10 mg · kg · h throughout the surgery. A dose of 100 mg/kg was placed in the cardiopulmonary bypass prime. A total of 16 to 18 samples were obtained from all patients throughout surgery. Plasma TXA concentrations were measured by high-performance liquid chromatography and modeled under a nonlinear mixed-effects framework with a two-compartment structural model. Cardiopulmonary bypass had a statistically significant impact on all pharmacokinetic parameters. Age was a better covariate than body weight, affecting both the distribution and the elimination of TXA. However, weight performed well in some cases. Other covariates including body surface area, pump prime volume, ultrafiltrate volume, and body temperature did not improve the model. This TXA pharmacokinetic analysis is reported for the first time in neonates and young children undergoing complex cardiac surgeries with cardiopulmonary bypass. Dosing recommendations are provided as guidance for maintaining desired target concentrations.

Population Pharmacokinetics of Tranexamic Acid in Paediatric Patients Undergoing Craniosynostosis Surgery

Tranexamic acid (TXA) effectively reduces blood loss and transfusion requirements during craniofacial surgery. The pharmacokinetics of TXA have not been fully characterized in paediatric patients and dosing regimens remain diverse in practice. A mixed-effects population analysis would characterize patient variability and guide dosing practices. The objective of this study was to conduct a population pharmacokinetic analysis and develop a model to predict an effective TXA dosing regimen for children with craniosynostosis undergoing cranial remodelling procedures. The treatment arm of a previously reported placebo-controlled efficacy trial was analysed. Twenty-three patients with a mean age 23 ± 19 months received a TXA loading dose of 50 mg/kg over 15 min at a constant rate, followed by a 5 mg/kg/h maintenance infusion during surgery. TXA plasma concentrations were measured and modelled with a non-linear mixed-effects strategy using Monolix 4.1 and NONMEM(®) 7.2. TXA pharmacokinetics were adequately described by a two-compartment open model with systemic clearance (CL) depending on bodyweight (WT) and age. The apparent volume of distribution of the central compartment (V1) was also dependent on bodyweight. Both the inter-compartmental clearance (Q) and the apparent volume of distribution of the peripheral compartment (V2) were independent of any covariate. The final model may be summarized as: CL (L/h) = [2.3 × (WT/12)(1.59) × AGE(-0.0934)] × e(η1), V1 (L) = [2.34 × (WT/12)(1.4)] × e(η2), Q (L/h) = 2.77 × e(η3) and V2 (L) = 1.53 × e(η4), where each η corresponds to the inter-patient variability for each parameter. No significant correlation was found between blood volume loss and steady-state TXA concentrations. Based on this model and simulations, lower loading doses than used in the clinical study should produce significantly lower peak concentrations while maintaining similar steady-state concentrations. A two-compartment model with covariates bodyweight and age adequately characterized the disposition of TXA. A loading dose of 10 mg/kg over 15 min followed by a 5 mg/kg/h maintenance infusion was simulated to produce steady-state TXA plasma concentrations above the 16 μg/mL threshold. This dosing scheme reduces the initial high peaks observed with the larger dose of 50 mg/kg over 15 min used in our previous clinical study.

Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass*

We conducted a study to assess pharmacokinetics of high-dose tranexamic acid for 24 h after administration of the drug in patients undergoing cardiac surgery with cardiopulmonary bypass. High-dose tranexamic acid involved a bolus of 30 mg.kg(-1) infused over 15 min followed by a 16 mg.kg(-1) .h(-1) infusion until chest closure with a 2 mg.kg(-1) load within the pump prime. Tranexamic acid followed first-order kinetics best described using a two-compartment model, with a total body clearance that approximated the glomerular filtration rate. Mean plasma tranexamic acid concentrations during the intra-operative period and in the first 6 postoperative hours were consistently higher than the suggested threshold to achieve 100% inhibition and 80% inhibition of tissue plasminogen activator. With recent studies implicating high-dose tranexamic acid as a possible aetiology of postoperative seizures following cardiac surgery, the minimum effective yet safe dose of tranexamic acid in high-risk cardiac surgery needs to be refined.